IFN-β Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality

• Published in: American journal of respiratory cell and molecular biology Vol. 59; no. 1; pp. 45 - 55
• Main Authors: Hiruma, Takahiro, Tsuyuzaki, Hitoshi, Uchida, Kanji, Trapnell, Bruce C, Yamamura, Yoshiro, Kusakabe, Yoshiomi, Totsu, Tokie, Suzuki, Takuji, Morita, Shigeki, Doi, Kent, Noiri, Eisei, Nakamura, Kensuke, Nakajima, Susumu, Yahagi, Naoki, Morimura, Naoto, Chang, Kyungho, Yamada, Yoshitsugu
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.07.2018
• Subjects: Alveoli; Animals; Bacterial infections; Cecum; Cytokines; Cytokines - metabolism; Disease Models, Animal; Edema; Humans; Immune clearance; Immunity, Innate - drug effects; Immunosuppression; Infections; Inflammation; Interferon-beta - pharmacology; Interferon-beta - therapeutic use; Interleukin 10; Leukocytes (neutrophilic); Lung Injury - blood; Lung Injury - drug therapy; Lung Injury - etiology; Lung Injury - physiopathology; Lungs; Macrophages; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - pathology; Male; Mice, Inbred C57BL; Models, Biological; Mortality; Neutrophils; Nitric oxide; Original Research; Pathogenesis; Phagocytosis; Pneumonia; Pneumonia - blood; Pneumonia - complications; Recruitment; Respiratory distress syndrome; Respiratory Distress Syndrome - blood; Respiratory Distress Syndrome - drug therapy; Respiratory Distress Syndrome - mortality; Respiratory Distress Syndrome - physiopathology; Rodents; Sepsis; Sepsis - blood; Sepsis - drug therapy; Sepsis - physiopathology; Signal Transduction - drug effects; Survival Analysis; Trachea; Treatment Outcome; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Viral infections; β-Interferon; United States > US; bacterial pneumonia; IFN-β; innate immunity; immune suppression; acute lung injury
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2017-0261OC

IFN-β is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-β for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-β 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-β reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-β improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.